Many of the specific molecular interactions that occur between the malarial parasite and its host, including cytoadherence, rosetting, and erythrocyte invasion, are mediated by parasite ligands encoded by proteins of the DBL-domain (Duffy binding like) superfamily. The DBL- domain is a cysteine rich domain with both conserved and variable features, and has been demonstrated to encode the ligand for the erythrocyte receptors glycophorin-A and the Duffy antigen. In the process of erythrocyte invasion P. falciparum is capable of utilizing several distinct pathways involving at least three different erythrocyte receptors. The only P. falciparum ligand known to mediate invasion by one of these pathways is EBA-175, a DBL-domain protein that binds to glycophorin-A. The hypothesis to be tested in this proposal is that several newly identified proteins of the DBL-domain family also function as ligands for erythrocyte receptors during invasion. The characterization of these proteins will involve determining their location within the parasite by fluorescence, electron and confocal microscopy and testing the ability of these proteins to bind erythrocytes. Preliminary investigation of the identity of the host receptor for these ligands will also be conducted, utilizing the binding regions expressed in a heterologous system, and assaying their ability to bind enzymatically modified erythrocytes, or those genetically deficient in defined surface molecules. The potential of using knockout parasites lacking the genes for these putative erythrocyte binding proteins will also be investigated. The extent to polymorphism within the genes encoding proteins shown to play a role in invasion will be investigated to suggest whether these proteins may be adapting to immune pressure or receptor heterogeneity. Finally, conserved features within the DBL-domains of the erythrocyte binding proteins will be exploited to identify additional members of this gene family which may also be involved in invasion.